This Program Project Grant application presents five interactive laboratory projects and two cores dedicated to making progress against human breast cancer by studying mouse models. It achieves synergy and an economy of effort by sharing existing strains, collaboratively developing new strains, designing and using an Imaging Core, discovering and applying new methods for genotyping and phenotyping, and the execution of therapeutic trials in mice using P01-developed reagents. Active cancer clinicians in the P01 are committed to assuring a meaningful impact on clinical thinking, education, and research. Project 1 focuses on the genes implicated in mammary cancer formation and progression, applying avian retroviral vector-based delivery of genes to mammary cells in vivo and iin vitro. Project 2 delineates the effects of the loss of TGF.'s tumor-suppressive function in metastatic breast cancer cells and studies a lung metastasis gene expression signature, including Id genes, that mediates pulmonary metastasis in mouse and human. Project 3 will use Hsp90 inhibitors and selective inhibitors of PI3K and AKt to determine the role of PI3K/AKt signaling in cancer, and continue to explore joint Hsp90 and HER2 modulation, which has already led to a clinical advance. Project 4 will characterize mammary tumors and their lung metastases occurring in HDR-deficient mammary epithelium. It will evaluate genetic instability in diverse mouse models to define the DNA damage response in normal, repair-deficient and oncogene-induced mammary epithelium. Project 5 will examine the effects on tumor initiation, progression, and metastasis of conditional Id-family over-expression in murine mammary epithelial cells and cancer epithelial cells arising from several well-defined genetic backgrounds. In collaboration with other projects it will examine the tumor-initiating and metastatic properties of Id1-variant models, and continue to develop therapeutic agents. The Imaging Core supplies advanced imaging technology to these projects. Larry Norton and Joan Massague serve as Program Director and Co-Director, and a Leadership Core will offer expertise in molecular array technology and biostatistics.